Biology Reference
In-Depth Information
was associated with decreased general cognitive performance, memory impairments, and
atrophy of the hippocampus, a brain area that is key for learning and memory [Convit
et al.,
2003]. These findings support the view that metabolic substrate delivery may influence brain
structure and function, and that better lifetime management of blood sugar may improve
memory in old age and perhaps even reduce the risk of hippocampal damage and possibly
AD.
There is increasing evidence that insulin has metabolic, neurotrophic and
neuromodulatory actions in the brain [Gerozissis, 2003]. Although there is relatively little
insulin produced within the brain, peripheral insulin has been shown to cross the blood-brain
barrier via a receptor-mediated transport process [Plum
et al.,
2005]. In the brain, insulin
receptors are expressed by both astrocytes and neurons [Boyd
et al.,
1985; Zhu
et al.,
1990].
Neuronal insulin receptors are concentrated at synapses and are components of postsynaptic
densities [Abbott
et al.,
1999]. Such a localization of insulin receptors has suggested a role for
insulin in learning and memory processes. For example, insulin receptors are upregulated and
undergo translocation after spatial learning [Zhao and Alkon, 2001]. Insulin modulates the
activity of excitatory and inhibitory receptors, including glutamate and GABA receptors and
activates the Shc-Ras-MAPK (mitogen-activated protein kinase) pathway and the PI3K
(phosphatidylinositol 3-kinase)/PKC (protein kinase C) pathway, both of which are involved
in memory processing [Nelson and Alkon, 2005]. The incidence of insulin resistance, a
symptom of Type II diabetes, is associated with a higher prevalence of AD [Ott
et al.,
1996].
Many AD patients have abnormal insulin levels in the cerebrospinal fliud, suggesting altered
insulin processing. Insulin also regulates the phosphorylation of tau, a major component of
neurofibrillary tangles [Carro and Torres-Aleman, 2004]. Intracerebroventricular injection of
streptozotocin or depletion of neuronal insulin receptors produces AD-like effects [Hoyer and
Lannert, 1999]. Similarly, the insulin-related peptide insulin-like growth factor-1 is abundant
in the CNS and is essential for normal brain development, promoting neuronal growth,
dendritic arborisation and synaptogenesis [Bondy and Cheng, 2004]. A recent study has
found that insulin and insulin-like growth factor-1 increase the expression of
monocarboxylate transporter MCT2 in cultured cortical neurons via a common mechanism
involving a translational regulation [Chenal
et al.,
2007]. In this regard, MCT2 belongs,
together with the dendritic scaffolding protein PSD-95, to a class of synaptic proteins
regulated at the translational level under conditions leading to synaptic plasticity [Lee
et al.,
2005]. Considering the primary function of MCT2 as a carrier of alternative energy substrates
(lactate, pyruvate, ketone bodies) for neurons [Pierre and Pellerin, 2005], a possible role of
insulin- and insulin-like growth factor-1-induced enhancement of MCT2 expression in
neurons could be to constitute a reserve pool that is mobilized when necessary to ensure
adequate supply of energy substrates to fuel active synapses.
Cholesterol and apolipoprotein E
Cholesterol, like insulin, plays an important role in basic metabolic processes in
peripheral tissues and can act as a signaling molecule in the CNS in neuronal function
[Dietschy and Turley, 2001]. Levels of cholesterol in the brain are critical for synapse
formation and maintenance and recent studies indentify cholesterol as a limiting factor in
synaptogenesis [Koudinov and Koudinova, 2001]. One of insulin's main effects in the
periphery is to stimulate the activity of HMG-CoA reductase, which catalyses the rate-
limiting step in cholesterol biosynthesis. Another link between cholesterol and insulin is that
